Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPCs) and tumors from two melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated from cord blood-derived HSPCs and tumors from different donors, the aHM recapitulates a patient-specific tumor microenvironment (TME). When patient tumors were implanted on aHM, mHM and NOD/SCID/IL2rg-/- (NSG) cohorts, tumors appeared earlier and grew faster on NSG and mHM cohorts. We observed that immune cells differentiating in the aHM were relatively more capable of circulating peripherally, invading into tumors and interacting with the TME. A heterologous, human leukocyte antigen (HLA-A) matched cohort also yielded slower growing tumors than non-HLA-matched mHM, indicating that a less permissive immune environment inhibits tumor progression. When the aHM, mHM, and NSG cohorts were treated with immunotherapies mirroring what the originating patients received, tumor growth in the aHM accelerated, similar to the progression observed in the patients. This rapid growth was associated with decreased immune cell infiltration, reduced interferon gamma (IFNγ)-related gene expression, and a reduction in STAT3 phosphorylation, events that were replicated in vitro using tumor-derived cell lines. Implications: Engrafted adult HSPCs give rise to more tumor infiltrative immune cells, increased HLA matching leads to slower tumor initiation and growth, and continuing immunotherapy past progression can paradoxically lead to increased growth.

中文翻译：

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研究黑色素瘤自体人源化小鼠异种移植物的免疫治疗抗性

对免疫疗法的抵抗是一项重大挑战，人体模型的稀缺性阻碍了对潜在机制的识别。为了解决这一限制，我们构建了一个自体人源化小鼠 (aHM) 模型，其中包含造血干细胞和祖细胞 (HSPC) 以及两名黑色素瘤患者的肿瘤，这些患者正在接受免疫治疗。与由脐带血衍生的 HSPC 和来自不同供体的肿瘤生成的错配人源化小鼠 (mHM) 模型不同，aHM 概括了患者特异性肿瘤微环境 (TME)。当患者肿瘤被植入 aHM、mHM 和 NOD/SCID/IL2rg-/- (NSG) 组群时，肿瘤在 NSG 和 mHM 组群中出现得更早并且生长更快。我们观察到在 aHM 中分化的免疫细胞相对更有能力进行外周循环，侵入肿瘤并与 TME 相互作用。与非 HLA 匹配的 mHM 相比，异源人类白细胞抗原 (HLA-A) 匹配的队列也产生了较慢的肿瘤生长，这表明免疫环境不太容易抑制肿瘤进展。当 aHM、mHM 和 NSG 队列接受与原始患者接受的免疫疗法相同的免疫疗法时，aHM 中的肿瘤生长加速，类似于在患者中观察到的进展。这种快速生长与免疫细胞浸润减少、干扰素 γ (IFNγ) 相关基因表达减少和 STAT3 磷酸化减少有关，这些事件在体外使用肿瘤衍生细胞系复制。启示：移植的成人 HSPC 产生更多的肿瘤浸润性免疫细胞，增加的 HLA 匹配导致较慢的肿瘤起始和生长，